X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia

Background: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. Methodology/Principal Findings: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. Conclusions: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease

Fisiopatologia dell'Emostasi e della Coagulazione

La capacità di controllare e mantenere all’interno dei vasi il flusso del sangue dopo un danno vasale è deputata a un complesso di eventi fisiologici denominati nel loro insieme processo emostatico-emocoagulatorio, mediante la formazione del trombo emostatico o coagulo. Il coagulo è una massa fibro-spugnosa di consistenza gelatinosa costituito da fibrina entro cui vengono trattenuti gli elementi figurati del sangue. Esso si forma attraverso una serie di complesse reazioni enzimatiche a cascata quando il sangue fuoriesce dal vaso, all’interno o all’esterno del corpo, in seguito a lesioni dell’endotelio. In tale processo si possono distinguere due fasi, una cronologicamente precoce, l’emostasi primaria, che porta alla formazione del cosiddetto “trombo bianco”, costituito principalmente da piastrine e scarsa presenza di fibrina, e una più tardiva, emostasi secondaria o coagulazione del sangue, con formazione del “trombo rosso” principalmente composto da un reticolo di fibrina con piastrine e globuli rossi imbrigliati al suo interno

Malattie emorragiche vascolari.

Le malattie emorragiche di origine vascolare sono causate da difetti nelle pareti dei vasi o del tessuto perivascolare, in assenza di deficienze piastriniche o della coagulazione. Di solito non sono gravi e si manifestano con ecchimosi o emorragie cutanee che terminano in breve tempo. Alterazioni delle pareti vasali o del tessuto perivascolare, in assenza di deficienze piastriniche o coagulatorie, Possono causare manifestazioni emorragiche per difetto dell’emostasi legato ad aumento della fragilità vascolare a livello venulare, capillare e arteriolare. Un’entità nosologica ben definita è la telangectasia emorragica ereditaria, mentre più incerta è la definizione delle porpore, che si possono distinguere in porpore non allergiche, a eziologia varia, e porpore allergiche, con il carattere di vasculiti a livello della microcircolazione sottocutanea

Automated assessment of lymphoid cells in chronic lymphocytic leukemia: correlation with prognostic features

In order to correlate the presence of large unstained cells (LUC) with clinical staging and prognosis, a quantitative cytometric analysis of leucocyte popula-tions from 88 patients with B-CLL was performed us-ing a Technicon H 6000 multichannel automated flow system. The results showed a significant increase in LUC num-ber, in the percentage of LUC to white cells and LUC to lymphocyte ratio in stage II (according to Rai classification) and in stage B (according to Work-shop on CLL staging system) patients. Our data analysis further revealed that chemothe-rapy was more effective in reducing the LUC popu-lation than that of small lymphocytes. Finally, an in-crease in LUC count and percentage was found to coincide with deterioration of clinical status. These data lead us to suggest that a high number of LUC, in patients with CLL, may represent an unfavou-rable prognostic factor

Flow cytochemical analysis of peripheral lymphocytes in chronic B-lymphocytic leukemia. Prognostic role of the blast count determined by the H1 system and its correlation with morphologic features.

Peripheral blood samples from 148 previously untreated patients with chronic B-lymphocytic leukemia (B-CLL) were analyzed with the Technicon H*1 flow cytometer. The absolute number and the percentage values of both LUCs (large unstained cells) and blasts were correlated with survival, as well as with well-known prognostic factors including morphological subtypes of lymphoid cells. Results showed that patients at the most advanced clinical stages (Rai: III and IV; Binet: C) had the highest percentage and count of both LUCs and blasts. Furthermore, the proportion of LUC positively correlated with the following prognostic factors: peripheral lymphocytosis (greater than 50 x 10(9)/l); marked splenomegaly (greater than 10 cm UCM); % of circulating prolymphocytes, % immunoblasts, and % LGL. Our data analysis further revealed that chemotherapy produced a greater reduction of both the LUCs and of the blast count than of that of small lymphocytes. An increase in LUC count was found to coincide with deterioration of clinical status (progressive changes in the clinical stages, occurrence of prolymphocytoid transformation). A rapid increase in blast count was found to occur in concomitance with the development of Richter's syndrome, and correlated positively with the number of peripheral immunoblasts determined by light microscopy. Moreover, a blast percentage higher than 7% had the strongest predictive relation to survival rate when compared with other hematological parameters (lymphocytosis greater than 50 x 10(9)/l, % of LUCs greater than 12%, LUC to lymphocyte ratio greater than 16%, LUCs count greater than 2.2 x 10(9)/l). In the light of these findings, it may be suggested that the presence both of larger proportions of LUCs and of blasts measured with the flow cytometry may be considered unfavorable prognostic factors in B-CLL. However, based on morphological and multivariate statistical analyses, the blast count proved to be the most important prognostic parameter determined by the H*1 system in B-CLL

Thrombotic risk in thalassemic patients.

Hemostatic parameters of 495 beta-thalassemic patients (421 with thalassemia major and 74 with thalassemia intermedia) were analyzed, to assess their association with the described thrombophilic condition and to verify the role of additional risk factors (e.g. persistent postsplenectomy thrombocytosis, insulin dependent diabetes mellitus, estrogen-progestin treatment and atrial fibrillation). The prevalence of thromboembolic accidents was 5.2% and in four patients (15.3%) inherited or acquired predisposing defects were recognized. The incidence of thromboembolic events and the associated relative risk due to hemocoagulative abnormalities in these patients are discussed

Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration

OBJECTIVE: Chronic venous disease (CVD) is the most common vascular disorder, progressing in approximately 10% of cases toward chronic venous leg ulceration, whereas the hemochromatosis gene (HFE) C282Y mutation is the most common recognized genetic defect in iron metabolism. Because CVD leads to local iron overload in the affected legs, we investigated whether two common HFE mutations could increase the risk of chronic venous leg ulceration. METHODS: This was a case-control study at the Vascular Diseases Center, University of Ferrara, Italy. From a cohort of 980 consecutive patients affected by severe CVD (CEAP clinical classes C4 to C6) we selected 238 cases with the exclusion of any other comorbidity factor potentially involved in wound etiology (group A). They were subdivided into group B, including 137 patients with ulcer (classes C5 and C6: 98 primary and 39 postthrombotic cases), and group C, including 101 cases with no skin lesions (class C4). They were completely matched for sex, age, and geographic origin with 280 healthy controls (group D). A total of 518 subjects were polymerase chain reaction genotyped for HFE mutations (C282Y and H63D). We assessed the risk of ulceration by comparing the prevalence of ulcer in homogenous cases with and without the HFE variants. Other main outcome measures were the sensitivity, specificity, and predictive values of the genetic test in CVD cases. RESULTS: C282Y mutation significantly increases the risk of ulcer in primary CVD by almost seven times (odds ratio, 6.69; 95% confidence interval, 1.45-30.8; P = .01). Application of the HFE test in primary CVD demonstrated increased specificity and positive predictive values (98% and 86%, respectively), with negligible sensitivity and negative predictive values. CONCLUSIONS: The overlap of primary CVD and the C282Y mutation consistently increases the risk of developing venous leg ulceration. These data, which have been confirmed in other clinical settings, suggest new strategies for preventing and treating primary CVD. CLINICAL RELEVANCE: The number of patients affected by primary CVD is so great that the vast majority of ulcers are also related to this common problem. On the other hand, there is not a reliable way for identifying in advance, from the broad base of primary CVD patients (20-40% of the general population), the high risk minority (10% of primary CVD cases) who will develop a venous ulcer. In such cases, a simple C282Y blood genetic test demonstrated an elevated specificity in predicting ulcer development (98%, CI 95%, 92.8-99.7). The genetic test could be applied starting from the C2 class, varicose veins, the most common situation observed in clinical practice. In perspective, the presence of the C282Y mutation would strengthen the indications and priorities for surgical correction of superficial venous insufficiency